1. Field of the Invention
This invention relates to a new a process for producing C-32 acylated derivatives of FK-506 type immunosuppressant macrolides. The process involves contacting the FK-506 macrolide with an acyl donor, in the presence of an immobilized enzyme on a support under conditions which acylate the C.sub.32 hydroxy group of the macrolide.
2. Brief Description of Disclosures in the Art
In 1983, the US FDA licensed cyclosporin, and extremely effective anti rejection drug that revolutionized the field of organ transplant surgery. The drug acts by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein.
As effective as the drug is in fighting transplantation rejection, it suffers drawbacks in causing kidney failure, liver damage and ulcers which in many cases can be very severe.
EPO Publication No. 0184162 to Fujisawa, describes a new macrolide immunosuppressant FK-506 which is reputed to be 100 times more effective than cyclosporin. The macrolide is produced by fermentation of a particular strain of Streptomyces tsukubaensis. Also described are the closely related FK-506 type macrolide immunosuppressant FK-520, FK-523, FK-525 produced by fermentation. More specifically, Fujisawa discloses on page 3 a generic compound (I) having the structure: ##STR1## wherein R.sup.1 is hydroxy or protected hydroxy,
R.sup.2 is hydrogen, hydroxy or protected hydroxy, PA1 R.sup.3 is methyl, ethyl, propyl or allyl, PA1 n is an integer of 1 or 2, and PA1 the symbol of a line and dotted line is a single bond or a double bond,
and salts thereof.
On page 32 of Fujisawa, there is disclosed a compound designated as FR-900506 having the structure: ##STR2##
A compound designated as FR-900525 is shown by Fujisawa on page 36 as having the structure: ##STR3##
The compound designated as FR-900520 by Fujisawa on page 55 is shown as having the structure: ##STR4##
A compound designated as FR-900523 is shown by Fujisawa on page 59 as having the structure: ##STR5##
EPO Publication No. 0,323,042 to Fisons also described various derivatives of FK-506 type macrolides.
It is known in the art that acylation of hydroxy groups can be conducted with an acyl donor in the presence of pyridine solvent. However, after the reaction, the pyridine is difficult to remove and generally n-heptane is added to azeotropically remove the pyridine from the product.
It is also known in the art that immobilized lipase enzymes can be used as acylating agents to catalyze the stereoselective acylation of racemic alcohols. See D. Bianchi et al, J. Org. Chem.,1988, vol 53, pp. 5531-5534. However, there is no suggestion that, where two or more available hydroxy groups are present in a large macrolide, i.e. FK-506, there may be a selectivity involved in the acylation.
What is desired is a simple, convenient method to selectively acylate the C-32 hydroxy function in FK-506 type macrolides without requiring the need for using pyridine, which is an environmental hazard.